ENDOGENOUS NEUROPROTECTION IN GLAUCOMA

 描述(申请人提供)：提高原发性开角型青光眼患者的视网膜神经节细胞(RGC)存活率是这种疾病患者的基本治疗目标，但到目前为止，试图降低手术或药物继发的眼压(IOP)是唯一临床批准的方法。直接保护视网膜节细胞免受青光眼损伤的初级神经保护疗法是理想的，但尚未进入临床，这主要是因为定义这种疾病的复杂的泛细胞病理学可能需要一种能够同时作用于多种损伤机制的多效性治疗。考虑到它在视网膜缺血和光毒性的临床前模型中被证明有效的记录，以及对心肌缺血和中风的条件反射的临床试验，通过非损伤性应激诱导适应性的、多因素的“条件反射”反应可能是一种这样的治疗方法。事实上，我们最近表明，在诱导3周的实验性青光眼之前，将小鼠暴露在一系列轻微的系统性低氧应激中，可以提供对RGC胞体和轴突的强大保护。在此提供的初步功能和形态发现证明，即使在疾病发作后出现重复的低氧刺激，也同样具有强大的保护作用。这种对青光眼“后处理”的表观遗传反应形成了本应用的基础，我们的研究将以以下具体目标为指导。具体目标1：使用我们的实验性青光眼诱导模型，验证重复低氧后处理(HX-Post)对视网膜神经节细胞的结构和功能保护随着疾病和治疗的进展而持续的假设。具体目的2：在我们的诱导性青光眼模型中，验证相关假设，即临床批准的药物去铁胺(DFX-Post)的重复药物后处理也将对视网膜节细胞提供持续的形态和功能保护。DFX通过稳定转录因子缺氧诱导因子-1α(HIF-1α)来保护视网膜节细胞的假说也将得到验证。具体目标3：在青光眼的DBA/2J遗传模型中，测试在7.5-12.0个月龄期间使用HX-Post和DFX-POST将积极影响终末期RGC疾病表型(结构和功能、胞体和轴索)的假设。具体目标4：利用遗传学和药理学方法，在我们的诱导模型中验证HX-Post介导的假设严重依赖于HIF-1α基因靶标CCL2(MCP-1)。记录继发于重复的生理学或药理学后处理的两个不同的青光眼模型中RGC功能和结构的持续改善，将提供强有力的概念证明，翻译上有希望的证据表明，可以激活一系列基于先天表观遗传学的保护反应，其中一些我们将在这里揭示，以保护人类青光眼的RGC。

 DESCRIPTION (provided by applicant): Enhancing retinal ganglion cell (RGC) survival in primary open-angle glaucoma is the fundamental treatment goal for patients with this disease, but to date, attempts to reduce intraocular pressure (IOP) secondary to surgery or drugs is the only clinically-approved approach. Primary neuroprotective therapies that directly protect RGCs from glaucomatous injury are desired, but have yet to be advanced to the clinic, largely because the complex, pan-cellular pathology that defines this disease will likely require a pleiotropic therapy capable of acting on multiple injury mechanisms concomitantly. Inducing an adaptive, multi-factorial "conditioning" response by a noninjurious stress may represent one such therapeutic approach, given its track record of demonstrated efficacy in preclinical models of retinal ischemia and phototoxicity, and the run of clinical trials of conditioning for myocardial ischemia and stroke. In fact, we recently showed that exposing mice to a series of mild systemic hypoxic stresses prior to inducing a 3-wk period of experimental glaucoma afforded robust protection of RGC soma and axons. Preliminary functional and morphologic findings provided herein document similarly robust protection even when the repetitive hypoxic stimulus is presented after disease onset. This epigenetic response to glaucoma "postconditioning" forms the basis of the present application, and our studies will be guided by the following specific aims. Specific Aim 1: Using our inducible model of experimental glaucoma, test the hypothesis that the structural and functional protection afforded RGCs by repetitive hypoxic postconditioning (HX-Post) is sustained as the disease and treatment progress. Specific Aim 2: In our inducible glaucoma model, test the related hypothesis that repetitive pharmacologic postconditioning with the clinically-approved drug deferroxamine (DFX-Post) will also afford sustained morphologic and functional protection of RGCs. The hypothesis that DFX protects RGCs via stabilization of the transcription factor hypoxia-inducible factor-1α (HIF-1α) will alsobe tested. Specific Aim 3: In the DBA/2J genetic model of glaucoma, test the hypotheses that HX-Post, and DFX-post, administered between 7.5-12.0 months of age, will positively impact 'end-stage' RGC disease phenotypes (structural and functional, somal and axonal). Specific Aim 4: Using genetic and pharmacologic approaches, test in our inducible model the hypothesis that HX-Post-mediated is critically dependent on the HIF-1α gene target CCL2 (MCP-1). Documenting sustained improvements in RGC function and structure in two distinct glaucoma models secondary to repetitive physiologic or pharmacologic postconditioning will provide strong proof-of-concept, translationally-promising evidence for the notion that a spectrum of innate epigenetics-based protective responses, some of which we will reveal here, can be activated for RGC protection in human glaucoma.